Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle

Traditionally, the central nervous system (CNS) was viewed as an immunologically-privileged site, which was interpreted as the complete absence of immune surveillance of this tissue [1]. The theoretical basis of these considerations were that CNS homeostasis, which is required for the proper communication of neurons, would not tolerate routine immune cell patrolling in their search for relevant antigens. Experimental findings supporting this notion were that allo- and xenogenic (from different species) tissue grafts, when transplanted into the CNS are much less efficiently rejected by the recipient when compared to transplantation to orthotopic (original) sites. Additionally, the CNS parenchyma is devoid of cells constitutively expressing MHC class I and II and therefore the molecules required by T cells to recognize their antigen. In addition, the CNS lacks lymphatic vessels and thus the commonly established pathways of the afferent communication arm of the immune system. Finally, it was thought that the efferent arm of the immune system to the CNS was completely blocked by the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) establishing the barriers between the changing blood milieu and the CNS. The view of immunological ignorance of the CNS has, however, been in conflict with observations by Medawar and colleagues that an allogenic tissue graft into the brain, which would be tolerated in a naive host, was readily rejected in a recipient which was sensitized to the allo-antigens before the transplantation [2]. These observations suggested that T cells activated outside the CNS found a way across the brain-barriers and mounted an immune response within the CNS. Subsequent observations in a number of immune-mediated CNS pathologies including chronic inflammatory diseases such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), made it obvious that the view of immune privilege